Amyotrophic lateral sclerosis ( ALS ) is a rapidly progressing neurodegenerative disease that is characterized by motor neuron loss and that leads to paralysis and death 2-5 years after disease onset.
Nearly all patients with amyotrophic lateral sclerosis have aggregates of the RNA-binding protein TDP-43 in their brains and spinal cords, and rare mutations in the gene encoding TDP-43 can cause amyotrophic lateral sclerosis.
There are no effective TDP-43-directed therapies for amyotrophic lateral sclerosis or related TDP-43 proteinopathies, such as frontotemporal dementia.
Antisense oligonucleotides ( ASOs ) and RNA-interference approaches are emerging as attractive therapeutic strategies in neurological diseases.
Indeed, treatment of a rat model of inherited amyotrophic lateral sclerosis ( caused by a mutation in Sod1 ) with antisense oligonucleotides against Sod1 has been shown to substantially slow disease progression.
However, as SOD1 mutations account for only around 2-5% of ALS cases, additional therapeutic strategies are needed.
Silencing TDP-43 itself is probably not appropriate, given its critical cellular functions.
Researchers have presented a promising alternative therapeutic strategy for amyotrophic lateral sclerosis that involves targeting ataxin-2.
A decrease in ataxin-2 suppresses TDP-43 toxicity in yeast and flies, and intermediate-length polyglutamine expansions in the ataxin-2 gene increase risk of amyotrophic lateral sclerosis.
Researchers have used two independent approaches to test whether decreasing ataxin-2 levels could mitigate disease in a mouse model of TDP-43 proteinopathy.
First, they crossed ataxin-2 knockout mice with TDP-43 ( also known as TARDBP ) transgenic mice. The decrease in ataxin-2 reduced aggregation of TDP-43, markedly increased survival and improved motor function.
Second, in a more therapeutically applicable approach, they administered antisense oligonucleotides targeting ataxin-2 to the central nervous system of TDP-43 transgenic mice. This single treatment markedly extended survival. Because TDP-43 aggregation is a component of nearly all cases of amyotrophic lateral sclerosis, targeting ataxin-2 could represent a broadly effective therapeutic strategy. ( Xagena )
Becker LA et al, Nature 2017; Epub ahead of print